Naturally occurring nondeletional mutations affecting the distal CCAAT box of the human -globin gene promoter result in hereditary persistence of fetal hemoglobin in adult life. Although the distal CCAAT box is the target of several factors, including CP1/NFY, CDP, GATA-1 and NFE3, only NFE3 binding activity is consistently sensitive to well characterized mutations in this region such as G A, C T, and 13 hereditary persistence of fetal hemoglobin. We extensively characterized the binding specificities of NFE3 and demonstrated that NFE3 has unique properties with respect to other CCAAT box-binding proteins. Affinity-purified NFE3 from erythroid K562 cells binds the distal but not the proximal human -globin CCAAT box, the single CCAAT box of the human -globin promoter, and the proximal CCAAT box of the evolutionarily related Galago crassicaudatus -globin gene. Within the -globin CCAAT box, NFE3 represents the major and almost exclusive binding activity. Disruption of such a binding site essentially inactivates the -globin promoter, suggesting that NFE3 plays an important role in the embryonic expression of this gene.

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